Canagliflozin mediates mitophagy through the AMPK/PINK1/PARKIN pathway to alleviate isoprenaline-induced cardiac remodelling.

Heart failure has always been a prevalent, disabling, and potentially life-threatening disease. For the treatment of heart failure, controlling cardiac remodeling is very important. In recent years, clinical trials have shown that SGLT-2 inhibitors not only excel in lowering glucose levels but also demonstrate favorable cardiovascular protective effects. However, the precise mechanisms behind the cardiovascular benefits of SGLT-2 inhibitors remain elusive. In our current research, we assessed the impact of canagliflozin (CANA, an SGLT-2 inhibitor) on cardiac remodeling progression in mice, and preliminarily elucidated the possible mechanism of action of SGLT-2 inhibitor. Our results indicate that the administration of canagliflozin significantly attenuates myocardial hypertrophy and fibrosis and enhances cardiac ejection function in mice with isoprenaline (ISO)-induced cardiac remodeling. Notably, excessive mitophagy, along with mitochondrial structural abnormalities observed in ISO-induced cardiac remodeling, were mitigated by canagliflozin treatment, thereby attenuating cardiac remodeling progression. Furthermore, the differential expression of AMPK/PINK1/Parkin pathway-related proteins in ISO-induced cardiac remodeling was effectively reversed by canagliflozin, suggesting the therapeutic potential of targeting this pathway with the drug. Thus, our study indicates that canagliflozin holds promise in mitigating cardiac injury, enhancing cardiac function, and potentially exerting cardioprotective effects by modulating mitochondrial function and mitophagy through the AMPK/PINK1/Parkin pathway.

The Efficacy and Safety of Sacubitril-Valsartan for the Treatment of Heart Failure in Adults: A Meta-Analysis.

OBJECTIVE: The current meta-analysis reviews the different randomized controlled trials (RCTs) on the use of sacubitril-valsartan (SV) thoroughly and assesses its effectiveness and safety as a drug for heart failure. DATA SOURCES: Relevant articles for meta-analysis were searched from PubMed, MEDLINE, and Central databases using appropriate keywords. STUDY SELECTION AND DATA EXTRACTION: Studies were included as per the predefined PICOS criteria. Demographic summary and event data change in heart conditions after drug intake and adverse effects of drugs under both the SV and control arms were determined. The risk of bias and comparative drug efficiency in terms of diagnostic odds ratio (OR) and risk ratio (RR) were determined using RevMan software. DATA SYNTHESIS: Ten RCTs with total 18 164 heart failure patients were included according to the inclusion criteria from the year 2015 to 2022. Included studies have patients of different age groups treated with either SV or control. For the change in number of patients with heart conditions after drug intake, we obtained the pooled OR of 0.80 (95% CI, 0.71-0.91) and pooled RR of 0.92 (95% CI, 0.88-0.96). The OR value less than 1 is indicative of high efficiency of SV in lowering the number of heart patients. All these values are statistically significant (P < 0.05) and suggested better recovery of patients with SV as compared with the control drugs with minimal risk and side effects. CONCLUSIONS: The present evidence shows that SV is effective in the treatment of heart failure, reducing hospitalization and cardiovascular mortality, and that the adverse effects are comparable or fewer than those associated with other drugs used for this indication.

Fabrication of "Plug and Play" Channels with Dual Responses by Host-Guest Interactions.

The "Plug and Play" template can be individually or successively grafted by dual-responsive molecules on the α-CD modified channels by host-guest interactions and can be peeled off by UV irradiation. The artificial channels present six kinds of responses cycling among four states responding to three environment stimuli, as light, pH, and temperature.

Preclinical Characterization and In Vivo Efficacy of GSK8853, a Small-Molecule Inhibitor of the Hepatitis C Virus NS4B Protein.

The hepatitis C virus (HCV) NS4B protein is an antiviral therapeutic target for which small-molecule inhibitors have not been shown to exhibit in vivo efficacy. We describe here the in vitro and in vivo antiviral activity of GSK8853, an imidazo[1,2-a]pyrimidine inhibitor that binds NS4B protein. GSK8853 was active against multiple HCV genotypes and developed in vitro resistance mutations in both genotype 1a and genotype 1b replicons localized to the region of NS4B encoding amino acids 94 to 105. A 20-day in vitro treatment of replicons with GSK8853 resulted in a 2-log drop in replicon RNA levels, with no resistance mutation breakthrough. Chimeric replicons containing NS4B sequences matching known virus isolates showed similar responses to a compound with genotype 1a sequences but altered efficacy with genotype 1b sequences, likely corresponding to the presence of known resistance polymorphs in those isolates. In vivo efficacy was tested in a humanized-mouse model of HCV infection, and the results showed a 3-log drop in viral RNA loads over a 7-day period. Analysis of the virus remaining at the end of in vivo treatment revealed resistance mutations encoding amino acid changes that had not been identified by in vitro studies, including NS4B N56I and N99H. Our findings provide an in vivo proof of concept for HCV inhibitors targeting NS4B and demonstrate both the promise and potential pitfalls of developing NS4B inhibitors.

Design and synthesis of spirocyclic compounds as HCV replication inhibitors by targeting viral NS4B protein.

Two novel series of spirocyclic piperidine analogs appended to a pyrazolo[1,5-a]pyridine core were designed, synthesized and evaluated for their anti-HCV activity. A series of piperidine ketals afforded dispiro 6p which showed excellent in vitro anti-HCV activities (EC50 of 1.5nM and 1.2nM against genotype 1a and 1b replicons, respectively). A series of piperidine oxazolidinones afforded 27c which showed EC50's of 10.9nM and 6.1nM against 1a and 1b replicons, respectively. Both compounds 6p and 27c bound directly to non-structural NS4B protein in vitro (IC50's=10.2 and 30.4nM, respectively) and exhibited reduced potency in replicons containing resistance mutations encoding changes in the NS4B protein.

High-Strain-Rate Deformation Behavior of Co0.96Cr0.76Fe0.85Ni1.01Hf0.40 Eutectic High-Entropy Alloy at Room and Cryogenic Temperatures.

The deformation behaviors of Co0.96Cr0.76Fe0.85Ni1.01Hf0.40 eutectic high-entropy alloy (EHEA) under high strain rates have been investigated at both room temperature (RT, 298 K) and liquid nitrogen temperature (LNT, 77 K). The current Co0.96Cr0.76Fe0.85Ni1.01Hf0.40 EHEA exhibits a high yield strength of 740 MPa along with a high fracture strain of 35% under quasi-static loading. A remarkable positive strain rate effect can be observed, and its yield strength increased to 1060 MPa when the strain rate increased to 3000/s. Decreasing temperature will further enhance the yield strength significantly. The yield strength of this alloy at a strain rate of 3000/s increases to 1240 MPa under the LNT condition. Moreover, the current EHEA exhibits a notable increased strain-hardening ability with either an increasing strain rate or a decreasing temperature. Transmission electron microscopy (TEM) characterization uncovered that the dynamic plastic deformation of this EHEA at RT is dominated by dislocation slip. However, under severe conditions of high strain rate in conjunction with LNT, dislocation dissociation is promoted, resulting in a higher density of nanoscale deformation twins, stacking faults (SFs) as well as immobile Lomer-Cottrell (L-C) dislocation locks. These deformation twins, SFs and immobile dislocation locks function effectively as dislocation barriers, contributing notably to the elevated strain-hardening rate observed during dynamic deformation at LNT.

Integrated Bioinformatics-Based Analysis of Hub Genes and the Mechanism of Immune Infiltration Associated With Acute Myocardial Infarction.

Background: Acute myocardial infarction (AMI) is a fatal disease that causes high morbidity and mortality. It has been reported that AMI is associated with immune cell infiltration. Now, we aimed to identify the potential diagnostic biomarkers of AMI and uncover the immune cell infiltration profile of AMI. Methods: From the Gene Expression Omnibus (GEO) data set, three data sets (GSE48060, GSE60993, and GSE66360) were downloaded. Differentially expressed genes (DEGs) from AMI and healthy control samples were screened. Furthermore, DEGs were performed via gene ontology (GO) functional and kyoto encyclopedia of genes and genome (KEGG) pathway analyses. The Gene set enrichment analysis (GSEA) was used to analyze GO terms and KEGG pathways. Utilizing the Search Tool for Retrieval of Interacting Genes/Proteins (STRING) database, a protein-protein interaction (PPI) network was constructed, and the hub genes were identified. Then, the receiver operating characteristic (ROC) curves were constructed to analyze the diagnostic value of hub genes. And, the diagnostic value of hub genes was further validated in an independent data set GSE61144. Finally, CIBERSORT was used to represent the compositional patterns of the 22 types of immune cell fractions in AMI. Results: A total of 71 DEGs were identified. These DEGs were mainly enriched in immune response and immune-related pathways. Toll-like receptor 2 (TLR2), interleukin-1B (IL1B), leukocyte immunoglobulin-like receptor subfamily B2 (LILRB2), Fc fragment of IgE receptor Ig (FCER1G), formyl peptide receptor 1 (FPR1), and matrix metalloproteinase 9 (MMP9) were identified as diagnostic markers with the value of p < 0.05. Also, the immune cell infiltration analysis indicated that TLR2, IL1B, LILRB2, FCER1G, FPR1, and MMP9 were correlated with neutrophils, monocytes, resting natural killer (NK) cells, gamma delta T cells, and CD4 memory resting T cells. The fractions of monocytes and neutrophils were significantly higher in AMI tissues than in control tissues. Conclusion: TLR2, IL1B, LILRB2, FCER1G, FPR1, and MMP9 are involved in the process of AMI, which can be used as molecular biomarkers for the screening and diagnosis of AMI. In addition, the immune system plays a vital role in the occurrence and progression of AMI.

Role of apolipoprotein O in autophagy via the p38 mitogen-activated protein kinase signaling pathway in myocardial infarction.

OBJECTIVE: To explore the role and possible mechanisms of action of apolipoprotein O (APOO) in autophagy in Myocardial Infarction (MI) in vivo and in vitro. METHODS: Differential gene expression and single Gene Set Enrichment Analysis (GSEA) were used to evaluate MI-related candidate genes. Animal and cell MI models were established. Sh-APOO, si-APOO, and SB203580 were used to inhibit the expression of APOO or p38MAPK. Western blot and qRT-PCR were used to analyze the expression levels of the target protein or mRNA. Apoptosis was observed using the TUNEL assay. The plasma concentrations of CK-MB and cTn-I in humans and mice were determined. RESULTS: In the GSE23294 dataset, APOO mRNA was highly expressed in the left ventricle of mice with MI; GSEA revealed that APOO was positively correlated with p38MAPK, autophagy, and apoptosis. The plasma concentration of APOO in patients with MI was significantly higher than that in healthy subjects. The expression of APOO, Beclin-1, LC3, and Bax in mouse and AC16 cell MI models increased, while the level of Bcl-2 decreased. After silencing the APOO gene, the expression of APOO was downregulated; meanwhile, changes in autophagy, apoptosis and myocardial cell injury were reversed in vivo and in vitro. Furthermore, autophagy was alleviated after AC16 cells were treated with SB203580. CONCLUSIONS: The increased APOO expression in mouse and cell MI models may activate autophagy and apoptosis by regulating the p38MAPK signaling pathway, thus aggravating the myocardial injury.

PINK1/Parkin-mediated mitophagy in cardiovascular disease: From pathogenesis to novel therapy.

Cardiovascular disease(CVD)is one of the predominant causes of death and morbidity. Mitochondria play a key role in maintaining cardiac energy metabolism. However, mitochondrial dysfunction leads to excessive production of ROS, resulting in oxidative damage to cardiomyocytes and contributing to a variety of cardiovascular diseases. In such a case, the clearance of impaired mitochondria is necessary. Currently, most studies have indicated an essential role for mitophagy in maintaining cardiac homeostasis and regulating CVD-related metabolic transition. Recent studies have implicated that PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy has been implicated in maintaining cardiomyocyte homeostasis. Here, we discuss the physiological and pathological roles of PINK1/Parkin-mediated mitophagy in the cardiovascular system, as well as potential therapeutic strategies based on PINK1/Parkin-mediated mitophagy modulation, which are of great significance for the prevention and treatment of cardiovascular diseases.

Discovery of a novel series of cyclic urea as potent CCR5 antagonists.

A novel series of cyclic urea-based CCR5 antagonists was designed aiming to resolve instability issue in the fasted simulated intestinal fluid (FSIF) associated with the acyclic urea moiety in 1. This class of CCR5 compounds demonstrated high antiviral activities against HIV-1 infection in both HOS and PBL assays. Further evaluation of these compounds indicated that 16-R not only substantially enhanced its stability, but also exhibited excellent pharmacokinetics properties.

Discovery of novel pyridyl carboxamides as potent CCR5 antagonists and optimization of their pharmacokinetic profile in rats.

A novel series of pyridyl carboxamide-based CCR5 inhibitors was designed, synthesized, and demonstrated to be highly potent against HIV-1 infection in both HOS and PBL assays. Attempts to evaluate this series of compounds in a rat PK model revealed its instability in rat plasma. A hypothesis for this liability was proposed, and strategies to overcome this issue were pursued, leading to discovery of highly potent 40 and 41, which featured dramatically improved rat PK profiles.

Discovery of N-benzyl-N'-(4-pipyridinyl)urea CCR5 antagonists as anti-HIV-1 agents (II): modification of the acyl portion.

Modification of the acyl moiety in the CCR5 lead molecule 2 led to identification of several new classes of CCR5 antagonists. Antiviral activity and pharmacokinetic properties of the synthesized compounds were evaluated. Structure-activity relationship (SAR) derived from these studies further guided the optimization efforts, ultimately leading to the discovery of 36 with an acceptable drug-like profile.

Discovery of N-benzyl-N'-(4-pipyridinyl)urea CCR5 antagonists as anti-HIV-1 agents (I): optimization of the amine portion.

Several series of carbamate, urea and carboxamide-based CCR5 antagonists have been discovered via optimizations at the amine portion of lead compound 2. All compounds were evaluated for their antiviral activities. Lead urea 29 showed good pharmacokinetic properties, justifying further development of this series.

DME carbonylation over a HSUZ-4 zeolite.

Zeolite-catalyzed carbonylation of dimethyl ether to methyl acetate represents a new route to synthesize acetyls. A rod-shaped HSUZ-4 zeolite, with intersecting 10-member ring and 8-member ring channels, showed exceptionally high activity and durability, as compared to the HZSM-35 sharing a similar pore structure. The abundant openings of 8-member ring pores, as determined by the shape of HSUZ-4, facilitated the diffusion of the reactive molecules.

Rapid synthesis of platinum-ruthenium bimetallic nanoparticles dispersed on carbon support as improved electrocatalysts for ethanol oxidation.

Bimetallic nanocatalysts with small particle size benefit from markedly enhanced electrocatalytic activity and stability during small molecule oxidation. Herein, we report a facile method to synthesize binary Pt-Ru nanoparticles dispersed on a carbon support at an optimum temperature. Because of its monodispersed nanostructure, synergistic effects were observed between Pt and Ru and the PtRu/C electrocatalysts showed remarkably enhanced electrocatalytic activity towards ethanol oxidation. The peak current density of the Pt1Ru1/C electrocatalyst is 3731 mA mg-1, which is 9.3 times higher than that of commercial Pt/C (401 mA mg-1). Furthermore, the synthesized Pt1Ru1/C catalyst exhibited higher stability during ethanol oxidation in an alkaline medium and maintained a significantly higher current density after successive cyclic voltammograms (CVs) of 500 cycles than commercial Pt/C. Our work highlights the significance of the reaction temperature during electrocatalyst synthesis, leading to enhanced catalytic performance towards ethanol oxidation. The Pt1Ru1/C electrocatalyst has great potential for application in direct ethanol fuel cells.

Observation of deformation twinning and martensitic transformation during nanoindentation of a transformation-induced plasticity steel.

For the first time, deformation twinning and martensitic transformation were observed in retained austenite in a low-alloyed transformation-induced plasticity steel using nanoindentation in conjunction with electron backscattering diffraction and transmission electron microscopy. Dislocation glide, martensite formation and deformation twinning were correlated to pop-ins and deviation from linearity in the load-displacement curve. Deformation twinning was found to enhance the stability of retained austenite. This observation furthers our understanding of RA stability during straining of low-alloyed multiphase TRIP steel.

Role of apolipoprotein O in autophagy via the p38 mitogen-activated protein kinase signaling pathway in myocardial infarction

Abstract Objectives To explore the role and possible mechanisms of action of apolipoprotein O (APOO) in autophagy in Myocardial Infarction (MI) in vivo and in vitro. Methods Differential gene expression and single Gene Set Enrichment Analysis (GSEA) were used to evaluate MI-related candidate genes. Animal and cell MI models were established. Sh-APOO, si-APOO, and SB203580 were used to inhibit the expression of APOO or p38MAPK. Western blot and qRT-PCR were used to analyze the expression levels of the target protein or mRNA. Apoptosis was observed using the TUNEL assay. The plasma concentrations of CK-MB and cTn-I in humans and mice were determined. Results In the GSE23294 dataset, APOO mRNA was highly expressed in the left ventricle of mice with MI; GSEA revealed that APOO was positively correlated with p38MAPK, autophagy, and apoptosis. The plasma concentration of APOO in patients with MI was significantly higher than that in healthy subjects. The expression of APOO, Beclin-1, LC3, and Bax in mouse and AC16 cell MI models increased, while the level of Bcl-2 decreased. After silencing the APOO gene, the expression of APOO was downregulated; meanwhile, changes in autophagy, apoptosis and myocardial cell injury were reversed in vivo and in vitro. Furthermore, autophagy was alleviated after AC16 cells were treated with SB203580. Conclusions The increased APOO expression in mouse and cell MI models may activate autophagy and apoptosis by regulating the p38MAPK signaling pathway, thus aggravating the myocardial injury. HIGHLIGHTS APOO was highly expressed in the left ventricle of mice with myocardial infarction. Increasing of APOO may activate autophagy and apoptosis in myocardial infarction. The regulation of APOO in autophagy and apoptosis was regulated by p38MAPK signaling pathway.

Ondansetron given in the acute withdrawal from a repeated cocaine sensitization dosing regimen reverses the expression of sensitization and inhibits self-administration.

Male Sprague-Dawley rats were given two separate sensitizing regimens of cocaine (7 days on, 7 days off, 7 days on; 40 mg/kg/day s.c.) along with saline controls. Furthermore, animals also received the 5-HT(3) antagonist ondansetron (0.2 mg/kg s.c.) either during the second dosing regimen (3.5 h after each cocaine/saline injection) or during the first five days of the second withdrawal period. Animals were then challenged, on day 10 of withdrawal, with cocaine (7.5 mg/kg i.p.) and assessed by a behavioral rating scale and locomotor activity monitoring. The cocaine regimen induced behavioral and locomotor sensitization on day 10 of withdrawal, further, ondansetron inhibited sensitization regardless of whether given after each second cocaine regimen dose or during the second withdrawal period, although treatment 3.5 h after each cocaine injection appeared more effective. Ondansetron did not inhibit behavior in control animals. In a second experiment animals were trained to self-administer cocaine via an indwelling jugular catheter. After stable fixed-ratio responding (FR1 then FR2) they were given a progressive ratio (PR) schedule until PR each day was stable. During the first five days of withdrawal they were given either ondansetron (0.2 mg/kg s.c.) or saline injections. On day 10 of withdrawal the cocaine PR schedule was reinstated. The ondansetron treated rats showed only a non-significant decrease in break point. After day 2 of the PR session rats were again injected with either ondansetron (0.2 mg/kg s.c.) or saline, 3.5 h after each PR session for five days. Ondansetron inhibited cocaine self-administration on each of the following days. Ondansetron may be a useful treatment for cocaine addicts who have undergone previous sensitization periods.

Hepatitis C replication inhibitors that target the viral NS4B protein.

We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with the viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead 1a. The temptation to improve antiviral activity while compromising physicochemical properties was tempered by the judicial use of ligand efficiency indices during lead optimization. In this manner, compound 1a was transformed into (+)-28a which possessed an improved antiviral profile with no increase in molecular weight and only a modest elevation in lipophilicity. Additionally, we employed a chimeric "humanized" mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo. This successful proof-of-concept study suggests that drugs targeting NS4B may represent a viable treatment option for curing HCV infection.

Discovery of a potent boronic acid derived inhibitor of the HCV RNA-dependent RNA polymerase.

A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild-type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a subgenomic replication system for a series of non-nucleoside boron-containing HCV RNA-dependent RNA polymerase (NS5B) inhibitors are described. A summary of the discovery of 3 (GSK5852), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.